2. Diagnosis and differential diagnosis

Gestational trophoblastic neoplasia (GTN) refers to the last three forms of GTD: invasive mole, choriocarcinoma, and PSTT/ETT. The components needed to diagnose postmolar GTN are one or more of the following:

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hCG plateau (<10% decrease) for four consecutive values over a period of 3 weeks.

hCG rise of 10% or greater for three values over 2 weeks.

hCG persistence 6 months after molar evacuation.

histopathologic diagnosis of choriocarcinoma.

presence of metastatic disease.

3. Management

A. What therapies should you initiate immediately (ie, emergently)?

Treatment of GTN is based on classification into risk groups defined by FIGO anatomic stage and modified WHO Risk-Factor Score. The FIGO stage ( Table I ) is designated by a Roman numeral followed by the modified WHO Risk-Factor Score ( Table II ) designated by an Arabic numeral.
Table I.n

Low-Risk GTN

Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN can be treated with single-agent methotrexate or actinomycin D chemotherapy. Approximately 20-30% of low-risk patients will develop resistance to the initial chemotherapeutic agent, but about 90% will be cured by the use of sequential single-agent chemotherapy. Ultimately, approximately 5-15% of patients will require multiagent chemotherapy with or without surgery to achieve remission. Cure rates should approach 100% for this group of patients.

B. What should the initial definitive therapy for the cancer be?

Initial treatment protocols

Methotrexate 0.4 mg/kg (maximum 25 mg) IM or IV push daily for 5 days every other week seems to be the most effective treatment protocol with 87-93% primary remission rates in retrospective observational studies. Another methotrexate regimen gives slightly higher doses of methotrexate (1.0 mg/kg) IM every other day, alternating with folinic acid (0.1 mg/kg) over 8 days with at least 1 week between courses. This protocol is reported to have decreased toxicity, but is more inconvenient and has been associated with increased need to change chemotherapy to achieve remission (primary remission rates of 74-90%).

Actinomycin D is an alternative to methotrexate, but has more toxicity (nausea, alopecia) and injures local tissue if IV extravasation occurs. Actinomycin D (10-12 mcg/kg IV daily for 5 days every other week) has been used in the presence of methotrexate resistance or in patients who have hepatic or renal compromise or effusions contraindicating use of methotrexate. The primary remission rate for the daily actinomycin D regimen is 77-94%.

Another actinomycin D regimen is the “pulse” protocol using a single 1.25 mg/m2 (max 2.0 mg) IV dose every 2 weeks. This regimen has a primary remission rate of 69-90%.

Single-agent chemotherapy with methotrexate or actinomycin D using one of the multiday dosing schedules is the preferred treatment for patients with low-risk metastatic disease. The weekly methotrexate or biweekly actinomycin D single-dose protocols should be limited to the treatment of nonmetastatic postmolar GTN.

Regardless of the treatment protocol used, chemotherapy is continued until hCG values have returned to normal and at least one course has been administered after the first normal hCG level. Chemotherapy is changed to an alternate single-agent regimen if hCG level plateaus above normal (<10% fall in three consecutive hCG values over 2 weeks) during treatment or if toxicity precludes an adequate dose or frequency of treatment.

Multiagent chemotherapy should be initiated if there is a significant elevation in hCG level (increase in hCG >10%), development of metastases, or resistance to sequential single-agent chemotherapy. Risk factors for single-agent chemotherapy resistance include older age, higher hCG levels, nonmolar antecedent pregnancy, clinicopathologic diagnosis of choriocarcinoma, presence of metastatic disease, and increasing FIGO score.

Hysterectomy may become necessary to remove persistent, chemotherapy-resistant disease in the uterus or in the treatment of uterine hemorrhage from tumor. Hysterectomy is the treatment of choice for PSTT. (See Placental Site Trophoblastic Tumor.) If future fertility is not desired, hysterectomy may be performed as adjuvant treatment with the start of chemotherapy to shorten duration of treatment. (See Future Fertility After GTN.)

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

Alternative low-risk GTN treatment protocols

Alternative regimens have been developed for actinomycin D and methotrexate ( Table III ).They typically combine higher doses with less frequent administration or use a combination of both agents sequentially; these regimens have been used in an effort to balance cost, toxicity, and efficacy. For example, single weekly IM doses of methotrexate (30-50 mg/m2) is a convenient protocol with lower toxicity and decreased cost, but it has the lowest reported response rates (49-74%). It is not an appropriate choice for metastatic disease or choriocarcinoma.
Table III.n

Chemotherapeutic Treatment of Low-Risk GTN

Similar to the methotrexate/folinic acid regimen described previously (see Initial Treatment Protocols), high-dose methotrexate (100 mg/m2 IV push, then 200 mg/m2 IV over 12 hours) followed by folinic acid rescue with the interval between doses reliant on post-treatment hCG trends has been associated with increased cost and need for second-line therapy, but an efficacy (69-90% remission rate) similar to the daily methotrexate regimen described in the previous section (see Initial Treatment Protocols).

B. What complications could arise as a consequence of the management – chemo, radiation and surgical?

Chemotherapy should be continued for two or three courses after first normal hCG. Adjuvant radiation or surgery may additionally be indicated. (See Adjuvant Radiotherapy and Surgery in High-risk GTN.) Approximately 30% of patients will fail first-line therapy or relapse. These patients are treated with platinum/etoposide-containing multiagent chemotherapy, often with surgical resection of persistent tumor. (See Second-line Treatment of Persistent or Recurrent High-risk GTN.)

C. What other therapies are helpful for reducing complications?

Adjuvant radiotherapy and surgery in high-risk GTN

Adjuvant surgical procedures, primarily hysterectomy and pulmonary resection for chemotherapy-resistant disease, as well as control of hemorrhage, are important components in the management of high-risk GTN. Approximately 50% of high-risk patients will require some surgical procedure during the course of treatment to effect cure.

In patients with central nervous system metastases, whole brain irradiation (3000 cGy in 200-cGy fractions) or surgical excision with stereotactic irradiation in selected patients is usually given simultaneously with systemic chemotherapy.

During radiation, the methotrexate dose in the EMA/CO protocol is increased to 1 g/m2 and 30 mg of folinic acid is given every 12 hours for 3 days starting 32 hours after the infusion begins ( Table IV ). Others advocate concurrent intrathecal with high-dose IV methotrexate therapy as part of multiagent chemotherapy as an alternative to brain irradiation.

Cure rates with brain metastases are 50-80% depending on symptoms as well as number, size and location of brain lesions.

5. Prognosis and outcome

A. What would you tell patient and family about the prognosis?

Second-line treatment of persistent or recurrent high-risk GTN

Approximately 30% of patients with high-risk GTN will have an incomplete response to first-line multimodal therapy or experience a relapse from remission. Salvage chemotherapy with regimens containing etoposide and a platinum drug combined with surgical excision of persistent tumor will result in cure in many of these patients.

In patients who have responded to EMA/CO but have plateauing low hCG levels or have a re-elevation of hCG after complete response to EMA/CO, the most appropriate therapy is EMA/EP substituting etoposide and cisplatin for cyclophosphamide and vincristine in the EMA/CO protocol ( Table IV ).

In patients who have developed methotrexate resistance, combination therapy containing etoposide and platinum with bleomycin, ifosfamide, or paclitaxel has been shown to be effective ( Table V ).
Table V.n

Chemotherapy for Refractory Metastatic High-Risk GTN or PSTT

B. "What if" scenarios

Placental site trophoblastic tumor

The rarity of PSTT makes studies examining etiology, risk factors, treatment, and long-term outcome difficult. For the most part, small case series compose the bulk of literature. The foundation for all stages of PSTT remains surgical management with hysterectomy and lymphadenectomy because of the propensity of PSTT to spread to the lymphatic system and their relative resistance to chemotherapy.

Chemotherapy is recommended in patients with metastatic disease or in patients with nonmetastatic disease who have risk factors for recurrence, such as time since antecedent pregnancy >2 years, vascular invasion, deep myometrial invasion, high mitotic index (>6/10 high-power fields), or tumor necrosis and/or persistently elevated postoperative serum hCG levels.

Chemotherapy is recommended in patients with metastatic disease or in patients with nonmetastatic disease who have risk factors for recurrence, such as time since antecedent pregnancy >2 years, vascular invasion, deep myometrial invasion, high mitotic index (>6/10 high-power fields), or tumor necrosis and/or persistently elevated postoperative serum hCG levels.

Although the optimal regimen remains to be defined, current clinical impression for first-line chemotherapy for PSTT is a platinum-containing regimen such as EMA/EP ( Table IV ) or TP/TE ( Table V ).

The largest retrospective study identified 62 patients with PSTT of a total of 35,550 patients diagnosed with GTD between 1976-2006 (representing 0.2%). Overall survival was 70%, with a recurrence-free survival of 73%. (See Schmid et al.).

The mainstay of therapy in this and other reports remains surgery. Of 34 patients with stage I disease, equal numbers were treated with surgery or surgery and chemotherapy. Overall survival at 10 years was similar for the two groups at 91% and 93%, respectively. Patients with stage II disease or greater were treated with surgery and chemotherapy, resulting in an overall survival at 10 years of 50%.

6. Follow-up surveillance and therapy management of recurrences

Reasons for treatment failure

Outcomes for patients who had failed initial therapy and were referred to a trophoblastic disease center have been reviewed. (See Lurain et al.). For patients treated primarily at a trophoblastic disease center, survival was 95% compared with 73% for patients treated secondarily. Analysis revealed that most referred patients had not received optimal primary chemotherapy, either in choice of single-agent and/or dosage and treatment schedules.

The most common cause of treatment failure was selection of a single-agent chemotherapy protocol to treat high-risk GTN (see High-risk GTN). The second most common reason for treatment failure was inappropriate use of the weekly IM methotrexate protocol (see Alternative Low-risk GTN Treatment Protocols) to treat patients with metastatic disease, risk score 7 or greater, and/or nonpostmolar choriocarcinoma.

Request for advice from or referral for treatment to clinicians with expertise in management of GTN is recommended for low-risk patients who fail single-agent chemotherapy and for any patient with high-risk disease.

Follow-up after treatment for GTN

Chemotherapy should be continued as noted above (see Low-risk GTN Initial Treatment Protocols and see High-risk GTN). Quantitative serum hCG levels should be obtained at 1-month intervals for 12 months after resolution of GTN. The risk of relapse is about 3% in the first year after completing therapy. Physical examinations should be performed every 6-12 months. Contraception should be maintained during treatment and for 1 year after completing chemotherapy, preferably using oral contraception.

Because of the risk of subsequent GTD, pelvic ultrasound should be performed in the first trimester to confirm a normal gestation, careful histopathologic evaluation of products of conception or placentas should be performed, and a 6-week postpartum quantitative hCG should be collected.

Future fertility after GTN

GTN occurs most frequently in women of reproductive age, many of whom remain interested in fertility after resolution of their GTN. Multiple studies have demonstrated that the most likely pregnancy outcome after fertility-sparing treatment for GTN is a successful term pregnancy.

Compared with the general population there does appear to be an increased incidence of stillbirth (approximately 1.5% vs 0.6%) and repeat molar pregnancy (0.6-2.0%) in women who have been treated with chemotherapy for GTN. The mechanisms resulting in these increases are not understood.

Pregnancies resulting in repeat molar gestation also have an increased risk of persistent GTN. An increase in the incidence of congenital anomalies after chemotherapy has not been seen. As noted previously, current recommendations for follow-up of GTN include contraception for 12 months subsequent to resolution of GTN.

In one study examining the outcomes of the first pregnancy after chemotherapeutic treatment for GTN, 37.5% of patients who conceived less than 6 months after chemotherapy had term pregnancies compared with 81.8% of patients who conceived after 12 months. (See Matsui et al.) The mechanisms resulting in this decrease remain to be elucidated.

What is the evidence for specific management and treatment recommendations?

Lurain, JR. “Gestational trophoblastic disease. II: classification and management of gestational trophoblastic neoplasia”. Am J Obstet Gynecol. vol. 204. 2011. pp. 11-18. (The second of a two-part series on GTD this article provides a cogent review and concise analysis for the rationale and methods for the treatment of GTN using risk stratification based on stage and a scoring system. The author is the head of a trophoblastic disease center in the United States and has published extensively on GTD.)

Schmid, P, Nagai, Y, Agarwal, R, Hancock, B, Savage, PM, Sebire, NJ. “Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study”. Lancet. vol. 374. 2009. pp. 48-55. (The authors, predominantly researchers from GTD centers in the UK, provide a retrospective analysis of diagnosis, management, and outcomes for the largest PSTT cohort published to date. They present data for 62 patients who were diagnosed with PSTT of 35,550 patients with GTD [0.2%] from 1976 through 2006. They aimed to estimate overall survival and recurrence-free survival at 10 years from initial treatment [70% and 73%, respectively].)

Matsui, H, Itsuka, Y, Suzuka, K, Yamazawa, K, Tanaka, N, Mitsuhashi, A. “Early pregnancy outcomes after chemotherapy for gestational trophoblastic tumor”. J Reprod Med. vol. 49. 2004. pp. 531-534. (Researchers from Chiba University Graduate School of Medicine, Japan, had previously published results of total pregnancy outcomes following GTN; they found that overall pregnancy outcomes after chemotherapy were comparable to the total Japanese population. First pregnancy outcomes were examined in this paper using the same retrospective cohort from 1974 to 2001. Results are comparable to those published by other groups and suggest that pregnancy is safe. They found similar pregnancy outcomes after 6 months following chemotherapy compared with waiting more time. Stillbirth rates in this cohort were similar to those in other groups, but these were not compared with the general population in this article [see Future Fertility After GTN].)

Lurain, JR, Hoekstra, AV, Schink , JC. ” Results of treatment of patients with gestational trophoblastic neoplasia referred to the Brewer Trophoblastic Disease Center after failure of treatment elsewhere (1979-2006)”. J Reprod Med. vol. 53. 2008. pp. 535-540. (The literature has shown that patients referred to a trophoblastic disease center where providers have more experience treating patients with GTN have had better results. Within this context, the authors at the Brewer Trophoblastic Disease Center analyze the outcomes of primary treatment and secondary treatment referrals focusing on the underlying reasons for primary treatment failure in the referral population.)

Hancock, BW, Seckl, MJ, Berkowitz, RS, Cole, LA. “Gestational trophoblastic disease”. April 2009. (Written and edited predominantly by members of the ISSTD, this book is updated and published online periodically. Comprehensive in its scope, the book includes chapters on the presentation, diagnosis, and management of GTD in the United States, United Kingdom, and Japan. General GTD topics (diagnosis and treatment) are featured; however, in addition, psychosocial aspects of GTD and future directions for diagnosis, pathophysiology, and patient care are covered.)

Lurain, JR, Singh, DK, Schink, JC. “Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stage II-IV, risk factor score > or = 7”. J Reprod Med. vol. 55. 2010. pp. 199-207. (With the a priori hypotheses that patients with higher FIGO stage and risk factor score are at higher risk for failure, researchers at the Brewer Trophoblastic Disease Center in the United States examined a retrospective cohort of 40 patients with high-risk GTN. The survival outcomes were favorable for patients treated both primarily and secondarily [92% vs 86%] at the Trophoblastic Center. They used recommended first-line and second-line therapy. All deaths were in patients with risk score 12 or greater [see Treatment of GTN].)

Lurain, JR, Schink , JC. “Importance of Salvage Therapy in the Management of High-Risk Gestational Trophoblastic Neoplasia”. J Reprod Med. vol. 57. 2012. pp. 219-224. (Recommendations are established for first-line treatment for high-risk GTN [see High-risk GTN]. Despite the success of these regimens a small percentage of patients fail or relapse. In this context, this article presents results of a retrospective analysis of salvage therapy in patients with high-risk GTN. Results are comparable to other groups and suggest a platinum/etoposide-based drug regimen should be implemented in these patients.)

Garrett, LA, Garner, EIO, Feltmate, CM, Goldstein, DP, Berkowitz, RS. “Subsequent pregnancy outcomes in patients with molar pregnancy and persistent gestational trophoblastic neoplasia”. J Reprod Med. vol. 53. 2008. pp. 481-486. (The authors at the New England Trophoblastic Disease Center and the Dana-Farber Cancer Institute updated previous published data that demonstrate pregnancy outcomes following complete moles, partial moles and persistent GTN. In agreement with other previously published data [including studies from this group], pregnancy outcomes are comparable to the general population [see Future Fertility After GTN]. These data were collected by survey; approximately 10% of surveys were returned with sufficient data for analysis.)